The ultimate goal of our Section is to understand how cellular and molecular changes produce changes in particular neurocircuits to convey negative emotional states that contribute to the motivation to seek drugs. Currently, we have been investigating the neurochemical and neuroanatomical basis underlying alcohol, heroin, and psychostimulant dependence. Alcohol: We investigated the effects of oxytocin on compulsive alcohol drinking. In this project, rats are trained to lever press for access to alcohol (i.e., operant conditioning). Another lever gives access to water. In this procedure, rats exhibit stable levels of drinking (nondependent) in daily 30 min sessions (about 30 lever presses for alcohol). Then, some of the animals are made dependent on alcohol via chronic, intermittent alcohol vapor exposure (dependent). This results in a dramatic increase in alcohol self-administration in the same period of time (more than 60 lever presses for alcohol in 30 min). Using this model, we observed that oxytocin (a neuropeptide) is capable of substantially reducing compulsive alcohol consumption observed in dependent animals, without disrupting the behavior of nondependent control animals (i.e., the effect is specific to alcohol dependence). This project is highly translational, as we are working to provide data as the basis for a clinical trial of oxytocin in alcohol dependent humans, to be conducted in collaboration with the NIAAA. Heroin: Experimental evidence from human patients, monkeys, and rats indicates that neutral cues can be associated with opioid withdrawal. Presentation of these cues alone can increase operant responding for access to heroin and this constitutes a model of compulsive drug seeking and taking. Here, we developed a rat model of conditioned heroin withdrawal using a heroin self-administration paradigm and naloxone-precipitated withdrawal paired with unique odor cues. We aim to identify the neural circuitry mediating the acquisition and expression of conditioned withdrawal cues. To achieve this we are using: 1. in vivo functional magnetic resonance imaging, and 2. molecular imaging (e.g., immunohistochemistry and in situ hybridization). Additionally, we are further characterizing behavioral responses following presentation of conditioned withdrawal cues in a variety of paradigms (e.g., pain) to understand how these cues affect behavior. Preliminary data indicate a number of cortical and subcortical brain regions to be specifically related to cues that were paired with negative emotional states of opioid withdrawal. Methamphetamine: Methamphetamine is a highly addictive stimulant that has been shown to be substantially detrimental to people suffering from methamphetamine addiction. There is currently no pharmacological treatment for methamphetamine abuse or relapse prevention. This study explores the effects of R-Modafinil, an FDA-approved wake-promoting agent that acts on monoamine transporters, and its analogues on methamphetamine self-administration. In this study, rats were trained to self-administer methamphetamine (0.05 mg/kg) intravenously in 1-h or 6-h sessions. Animals with daily access to the drug for 6 h progressively escalate their intake, whereas animals with access to the drug for 1 h exhibit stable drug intake levels over time. Upon escalated methamphetamine intake, the rats were given intraperitoneal injections of vehicle, modafinil or the DAT-selective analogues, JJC8-016, JJC8-089, and JJC8-091 and tested for methamphetamine self-administration. Thus far, we have data indicating that JJC8-016 and JJC8-091 are capable of reducing methamphetamine self-administration. Cocaine: Cocaine abuse affects approximately 1.7 million individuals nationwide per year and is characterized by patterns of excessive drug seeking and taking, including a preoccupation with obtaining the drug, repetitive seeking and taking of the drug, and a loss of control over drug intake. Compulsive-like cocaine taking and reinstatement of drug seeking (a model of drug relapse) occur in part through neuroadaptations of brain stress systems that mediate negative emotional states implicated in motivational processes required for maintaining the dependent drug state. The goal of the current research is to characterize the role of neuropeptides, including hypocretin/orexin and dynorphin in the mediation of cocaine intake and the reinstatement of drug seeking following extinction. To date, we have shown hypocretin- or dynorphin-receptor antagonism within target extended amygdala brain regions results in attenuation of drug taking and seeking. Future studies are employing adeno-associated viral vectors targeting the hrct or pdyn gene to silence transcription of the peptides in particular brain regions.